Coronary heart disease is a leading cause of death and injury worldwide. Following an acute myocardial infarction (MI), early restoration of blood flow is the most effective strategy for reducing the size of the MI. Paradoxically, restoring blood flow to the area of the heart that is affected by the diminished flow can, in itself, be harmful. This is called reperfusion injury and can, by some estimates, be responsible for up to 50% of the final size of the MI (Yellon D. M., Hausenloy D. J., Myocardial reperfusion injury. New England Journal of Medicine 2007, 357:1121). The final size of the MI ultimately determines how well the heart can function after a heart attack.
Myocardial ischemia-reperfusion injury is defined as myocardial injury caused by the ischemic injury combined with injury caused by the restoration of coronary blood flow after an ischemic episode. Ischemia-reperfusion injury is mediated by an influx of calcium ions and depletion of oxygen during an ischemic event, followed by reoxygenation and generation of reactive oxygen species during reperfusion (Piper, H. M., Abdallah, C., Schafer, C., The first minutes of reperfusion: a window of opportunity for cardioprotection. Annals of Thoracic Surgery 2003, 75:644; Yellon, D. M., Hausenloy, D. J., Myocardial reperfusion injury. New England Journal of Medicine 2007, 357:1121). It is postulated that the influx of calcium and the increase in free radicals triggers cell death, or programmed cell death (Chen, X., Zhang, X., Hubo, H., et al., Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent cell death in ventricular myocytes. Circ Res 2005, 97:1009; Lopes-Neblina, F., Toledo, A. H., Toledu-Pereyra, L. H. Molecular biology of apoptosis in ischemia and reperfusion. J Invest Surg 2005, 18:335). However, treatment of patients with acute myocardial infarction with antagonists that block the influx of calcium or with scavengers of the reactive oxygen species has yielded disappointing clinical outcomes (Yellon, D. M., Hausenloy, D. J., Myocardial reperfusion injury. New England Journal of Medicine 2007, 357:1121).
Another strategy for reducing ischemia-reperfusion injury is termed ischemic preconditioning. Short repeated bouts of ischemia followed by reperfusion will condition the myocardium to withstand a prolonged bout of ischemia (Otani, H., Ischemic preconditioning: From molecule mechanisms to therapeutic opportunities. Antioxidants & Redox Signaling, 2008, 10:207). However, intentionally occluding a patient's coronary artery is associated with undue risks and is therefore undesirable.
Thus, there is a significant need for new and more effective therapies and therapeutic agents for the treatment of ischemia and ischemia-reperfusion injuries resulting from cardiovascular disease and other conditions.